Growth hormone (GH) is secreted from the adenohypophysis (anterior pituitary gland) and has a variety of target tissues. GH has a common range of actions including somatic growth, differentiation and intermediary metabolism, effects that are mediated by GH-induced insulin-like growth factor-1 (IGF-1) (Bichell et al., 1992). IGF-1 is the major regulator of post-natal growth, and has both endocrine and paracrine action on different tissues.
GH induces transcription of different genes by binding to a membrane-associated receptor, the growth hormone receptor (GHR), which belongs to the superfamily of cytokine receptors (Graichen et al., 2003). These receptors lack intrinsic catalytic activity but are associated to cytosolic proteins with tyrosine-kinase activity. The receptors possess a single membrane-spanning domain and they exist as monomers that dimerize and become activated upon ligand binding. Several intracellular second messengers have been implicated in the signal transduction of GH, including calcium ions, phospholipase C, phospholipase A2, G-proteins, protein kinase C (PKC), Janus kinase 2 (JAK2) and signal transducer and activator of transcription (STAT) 1, 3 and 5 (Wood, 1996).
The signal transduction of GH has been investigated in the serine protease inhibitor (SPI) 2.1 gene, where activation is mediated through phosphorylation of JAK2 and STAT5 (Wood, 1996). When GHR becomes activated upon ligand binding the tyrosine kinase JAK2, which is associated to the GHR intracellular part, becomes phosphorylated and then phosphorylates the GHR itself. This leads to phosphorylation of STAT5, which homodimerizes, translocates to the nucleus and binds a specific sequence in the SPI 2.1 promoter called the GH-response element (GHRE), thereby activating gene transcription.
To regulate the numbers of GHR on the cell surface, the GHR is internalized in the cell by endocytosis and transported to lysosomal vesicles for destruction. However, the GHR has also been reported to get internalized and translocate to the nucleus upon GH-stimulation (Lobie, Wood 1994). It has been suggested that GHR itself might be involved in gene regulation. Interestingly, the nuclear translocation of both GH and the GHR is independent of JAK2 (Graichen et al., 2003), which suggests that this nuclear translocation might be an alternative signal transduction pathway independent of the JAK-STAT pathway.
Investigation of the two IGF-1 promoters reveals that no changes can be seen in DNA-protein interactions when rat hepatic IGF-1 is activated by GH (LeStunff et al., 1995, Thomas et al., 1994), and this together with the fact that GH induce a rapid activation of IGF-1 transcription (Bichell et al., 1992) suggests a GH-induced modification of pre-existing transcription factors bound to the DNA. One of the protein-bound DNA-sites in promoter 2 has been found to be a possible binding site for the transcription factor AP2, and the transcription factor OCT1 has also been suggested to bind to this promoter region (LeStunff et al., 1995). The transcription factor AP2 belongs to a family with four members, which all have been implicated as tissue-specific effectors of proliferation and differentiation during embryogenesis (Pfisterer et al., 2002; Werling and Schorle 2002). OCT1 is a ubiquitous transcription factor found in most mammalian cell types, where it activates transcription of a variety of genes.